Quinazolinones that inhibit the formation of tau oligomers and their method of use
Inventors
Davidowitz, Eliot J. • Moe, James G. • Reitz, Allen B. • Bian, Haiyan • Gluchowski, Charles • Hendrix, James • Yehaskel, Albert S. • McDonnell, Mark E. • Loughran, H. Marie
Assignees
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Publication Number
US-11472776-B2
Publication Date
2022-10-18
Expiration Date
Abstract
Novel quinazolinones useful as inhibitors of tau oligomer formation, useful for the treatment of neurodegenerative diseases and related conditions are disclosed. The invention also relates to the pharmaceutically acceptable salts of said compounds, processes for the preparation of said compounds, intermediates used in the preparation of said compounds, and pharmaceutical compositions containing said compounds. The invention further relates to methods of use of said compounds, salts of said compounds, and said compositions in treating neurodegenerative diseases and related conditions.
Core Innovation
The invention describes quinazolinone compounds and related compounds selected from formula groups (I), (IIa), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), and (VIIIa), including enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes. The compounds are defined by Markush formulas with substituent variables including X, A, R1, R2, R3a, R3b, R3c, R3d, R4a, R4ab, R5, R6, R7, R8, R9, R10, R11a, and R11b, where X is selected from N or CH and the substituents are assigned from defined groups with constraints on n and m.
The invention also provides pharmaceutical compositions and methods of treatment and diagnosis related to tau-oligomer-associated neurodegenerative diseases and Alzheimer’s disease. Therapeutic methods include administering a therapeutically effective amount of a compound or a composition to a patient in need, with pharmaceutically effective carriers, and optionally co-administering at least one additional agent for Alzheimer’s disease.
Diagnostic methods include administering an effective amount of a compound to a patient and scanning using PET or SPECT imaging with imaging probes. The provided content also describes compounds as inhibitors of tau oligomer formation and includes chemical structure depictions for multiple numbered compounds and additional compounds listed in Table 3.
Claims Coverage
The independent claim coverage centers on a broad structural definition of quinazolinone compounds across multiple formula sets (I–VIIIa) with detailed substituent constraints, while expressly including enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes. Additional coverage is provided by independent claim sets directed to pharmaceutical compositions, Alzheimer’s disease treatment, co-administration with at least one additional agent, and Alzheimer’s disease diagnosis using PET or SPECT imaging.
Multi-formula quinazolinone compound definition with tau-oligomer inhibition scope
A compound selected from the group consisting of compounds having formula (IIa), formula (I), formula (II), formula (III), formula (IIIa), formula (IV), formula (IVa), formula (V), formula (Va), formula (VI), formula (VIa), formula (VII), formula (VIIa), formula (VIII), and formula (VIIIa), including enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof, wherein X, A, and substituent variables R1, R2, R3a-R3d, R4a, R4ab, R5, R6, R7, R8, R9, R10, R11a, and R11b are defined by the recited selections and n and m are limited to defined values.
Pharmaceutical composition including the defined compound
A pharmaceutical composition comprising an effective amount of a compound according to the compound definitions, together with a pharmaceutically acceptable carrier.
Alzheimer’s disease treatment by administration of the defined compound
A method for treating Alzheimer’s disease comprising administering to a patient in need a therapeutically effective amount of a compound according to the compound definitions, optionally together with a pharmaceutically effective carrier.
Alzheimer’s disease treatment with co-administration of at least one additional agent
A method for treating Alzheimer’s disease comprising administering to a patient in need a therapeutically effective amount of a compound according to the compound definitions together with a pharmaceutically effective carrier and administering an effective amount of at least one additional agent selected from the specified list.
Alzheimer’s disease diagnosis using PET or SPECT imaging
A diagnostic method for Alzheimer’s disease comprising administering to a patient an effective amount of a compound according to the compound definitions and scanning the patient using PET or SPECT imaging with imaging probes.
The independent claim coverage spans broad structural definition of quinazolinone compounds across multiple formula sets with detailed substituent constraints, plus pharmaceutical composition, Alzheimer’s disease treatment, optional co-administration with at least one additional agent, and Alzheimer’s disease diagnosis using PET or SPECT imaging.
Stated Advantages
Provides ALA assay and CONFA assay IC50 table information for tau oligomer formation inhibitors.
Describes reduction of insoluble tau aggregates.
Supports in vivo tau pathology study endpoints.
Documented Applications
Tau oligomer formation inhibition, supported by ALA assay and CONFA assay IC50 table information.
Reduction of insoluble tau aggregates, referenced by a figure showing reduction of insoluble tau aggregates.
In vivo tau pathology study endpoints in animal models.
Treating Alzheimer’s disease by administering an effective or therapeutically effective amount of a compound together with a pharmaceutically effective carrier.
Treating Alzheimer’s disease by administering the compound together with a pharmaceutically effective carrier and administering an effective amount of at least one specified additional agent.
Diagnosing Alzheimer’s disease by administering an effective amount of the compound and scanning the patient using PET or SPECT imaging with imaging probes.
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